The present invention relates to oxazine compounds. In particular, the invention provides oxazine compounds and methods for their manufacture, which compounds are useful as photochromic compounds.
Various classes of photochromic compounds have been synthesized and suggested for use in applications in which reversible color changes or darkening is induced by sunlight. For example, spirooxazine and chromene compounds are known for excellent fatigue resistance. Additionally, photochromic 2,2-disubstituted [2H-1,4]-naphthoxazine compounds, such as those are disclosed in U.S. Pat. No. 5,801,243, are known. These compounds have better fatigue resistance than chromene compounds, but are disadvantageous in that methods for their preparation are extremely limited. Thus, a need exists for additional photochromic oxazine compounds that overcome the disadvantages of the known compounds.
The present invention provides oxazine compounds having aromatic, heteroaromatic, or aliphatic substituents at the 2 position of the oxazine moiety. Additionally, a one pot method with excellent yields is provided for producing the compounds.
In one embodiment, the invention provides a compound comprising the formula: 
wherein X is nitrogen or carbon;
R1 and R2 are each independently hydrogen, hydroxy, nitro, cyano, allyl, a linear or branched (C1-C20)alkyl, (C3-C20)cycloalkyl, (C1-C20)alkoxy, (C1-C20)alkylacetylenyl, phenylacetylenyl, (C1-C20)alkenyl, phenylvinyl, a halogen, a halo(C1-C20)alkyl, halo(C3-C20)cycloalkyl, halo(C1-C20)alkoxy, substituted with at least one halogen atom wherein the halogen is fluoro, chloro, bromo, or iodo, unsubstituted aryl, aryl substituted with (C1-C6)alkyl or (C1-C6)alkoxy or aryloxy, and preferably phenyl or naphthyl, unsubstituted heteroaryl or heteroaryl substituted with (C1-C6)alkyl or (C1-C6)alkoxy and preferably furyl, thienyl, pyrryl, indolyl, or pyridyl, arylalkyl or unsubtsituted heteroarylalkyl or heteroarylalkyl substituted with (C1-C6)alkyl or (C1-C6)alkoxy, substituted or unsubstituted nitrogen-containing heterocyclic ring, xe2x80x94N(R1)R2 or CON(R1)R2 wherein R1 and R2 are each independently hydrogen, (C1-C20)alkyl, (C3-C20)cycloalkyl, unsubstituted phenyl or phenyl substituted with (C1-C6)alkyl or (C1-C6)alkoxy, or a xe2x80x94OCOR or xe2x80x94COOR or xe2x80x94COR group wherein R is hydrogen, (C1-C20)alkyl, (C3-C20)cycloalkyl, or substituted or unsubstituted aryl or heteroaryl;
n is an integer from 0 to 4; and
A and Axe2x80x2 are each independently:
(a) a linear or branched (C1-C12)alkyl, (C3-C12)cycloalkyl, aryl(C1-C6)alkyl, heteroaryl(C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl, (C1-C12)alkoxy, halo(C1-C12)alkyl, (C1-C12)haloalkoxy, or (C1-C12)alkylthio wherein each of the aryl preferably are phenyl or naphthyl and each of the heteroaryl may be furyl, thienyl, pyrryl, indolyl, benzofuryl, benzothienyl, pyridyl, dibenzofuryl, dibenzothienyl, or carbazolyl;
(b) unsubstituted or mono- di- or tri-substituted aryl groups, such as phenyl and naphthyl;
(c) unsubstituted or mono-, or di-substituted heteroaromatic groups, such as furyl, thienyl, pyrryl, indolyl, benzofuryl, benzothienyl, pyridyl, dibenzofuryl, dibenzothienyl, carbazolyl;
(d) a group of either of the formulae: 
xe2x80x83wherein B is hydrogen, (C1-C12)alkyl, unsubstituted or mono- or di-substituted aryl, such as phenyl and naphthyl
xe2x80x83wherein each of said aryl and heteroaromatic substituents in (b), (c) and (d) are nitro, amino, cyano, hydroxy, epoxy, vinyl, allyl, hydroxyethoxy, methoxyethoxy, hydroxyethoxyethoxy, methoxyethoxyethoxy
xe2x80x83fluoro, chloro, bromo, or iodo, (C1-C12)alkyl, (C1-C12)alkoxy, (C1-C12)alkylaryl, aryl, aryloxy, aryl(C1-C12)alkyl, aryl(C1-C12)alkoxy, (C1-C12)alkoxyaryl, halo(C1-C12)alkyl, haloaryl, cyclo(C3-C12)alkyl; cyclo(C1-C12)alkoxy, aryloxyaryl, aryloxy(C1-C12)alkyl, aryloxy(C1-C12)alkoxy, acryloxy, methacryloxy, or
xe2x80x83a heterocyclic nitrogen-containing substituent, including, without limitation, N-(C1-C12)alkylpiperazino, N-aryl-piperizino, aziridino, indolino, pyrrolidino, pyrrolino, piperidino, (C1-C4)alkylpiperidino, di(C1-C4)alkylpiperidino, 4-piperidinopiperidino, morpholino, 2,6-di(C1-C4)alkylmorpholino, thiomorpholino, thioazolidino, tetrahydroquinolino, pyrryl, or xe2x80x94N(R1)R2 or CON(R1)R2 wherein R1 and R2 are each independently hydrogen, (C1-C12)alkyl, (C3-C12)cycloalkyl, phenyl, mono- or di-substituted phenyl, a xe2x80x94COR, xe2x80x94OCOR or xe2x80x94COOR group wherein R is hydrogen, (C1-C12)alkyl, (C3-C12)cycloalkyl, halo(C1-C6)alkyl, unsubstituted, mono- or di-substituted phenyl, or unsubstituted, mono- or di-substituted naphthyl, unsubstituted, mono- or di-substituted furyl or thienyl;
(e) unsubstituted or mono-substituted pyrazolyl, pyridyl, imidazolyl, pyrazolinyl, imidazolinyl, or acridinyl, wherein the substituents are each independently (C1-C6)alkyl, (C1-C6)alkoxy, fluoro, chloro, phenyl; or
(f) a group represented by either of the formulae: 
wherein C and D are each independently carbon, oxygen, (C1-C12)alkyl nitrogen, or (C1-C12)acyl nitrogen and R3 and R4 are each independently hydrogen or (C1-C12)alkyl.
In embodiments in which halogen is selected, preferably it is fluoro, chloro or bromo.
In a preferred embodiment, X is carbon or nitrogen, R1 and R2 are each independently hydrogen, nitro, cyano, allyl, fluoro, chloro, bromo, trifluoromethyl, trichloromethyl, pyrrolidino, piperidino, morpholino, phenyl, benzyl, a linear or branched (C1-C6)alkyl, (C1-C6)alkoxy, or a xe2x80x94OCOR or xe2x80x94COOR group wherein R is hydrogen, (C1-C6)alkyl, or (C3-C6)cycloalkyl;
n is an integer from 0 to 2; and
A and Axe2x80x2 are each independently:
(a) a linear or branched (C1-C6)alkyl, (C3-C6)cycloalkyl; aryl(C1-C4)alkyl heteroaryl(C1-C4)alkyl, or (C1-C6)alkoxy(C1-C6)alkyl;
(b) unsubstituted or mono- or di-substituted aryl, such as phenyl or naphthyl, preferably substituted in either or both the meta or para positions;
(c) unsubstituted or mono-substituted heteroaromatic groups, such as furyl, thienyl, pyrryl, indolyl, benzofuryl, benzothienyl, pyridyl, dibenzofuryl, dibenzothienyl, or carbazolyl;
wherein each of the aryl and heteroaromatic substituents in (b) and (c) are independently nitro, amino, cyano, hydroxy, epoxy, hydroxyethoxy, methoxyethoxy, hydroxyethoxyethoxy, methoxyethoxyethoxy, fluoro, chloro, bromo, or iodo, vinyl, allyl, trifluoromethyl, phenyl, (C1-C6)alkyl, (C1-C6)alkoxy, cyclo(C3-C6)alkyl, cyclo(C1-C6)alkoxy, (C1-C6))alkylamino, di(C1-C6)alkylamino, diarylamino, phenylacetylenyl, phenylvinyl, a heterocyclic nitrogen-containing substituent, including, without limitation, N(C1-C6)alkylpiperazino, N-aryl-piperizino, aziridino, indolino, pyrrolidino, pyrrolino, piperidino, (C1-C4)alkylpiperidino, di(C1-C4)alkylpiperidino, 4-piperidinopiperidino, morpholino, 2,6-di(C1-C4)alkylmorpholino, thiomorpholino, thioazolidino, tetrahydroquinolino, pyrryl, or a xe2x80x94N(R1)R2, CON(R1)R2 wherein R1 and R2 are each independently hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, phenyl, or xe2x80x94COR, xe2x80x94OCOR or xe2x80x94COOR wherein R is hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, or phenyl.
More preferably, X carbon or nitrogen; R1, R2 are each independently hydrogen, nitro, cyano, fluoro, chloro, bromo, pyrrolidino, piperidino, morpholino, phenyl, benzyl, (C1-C4)alkyl, or (C1-C4)alkoxy;
n is an integer from 0 to 2; and
A and Axe2x80x2 are each independently a linear or branched (C1-C4)alkyl, (C3-C6)cycloalkyl, unsubstituted or mono-, or di-substituted phenyl, preferably substituted in either or both the meta and para positions with a substituent selected from the group consisting of nitro, amino, acyl, cyano, methoxy, ethoxy, methoxyethoxy, fluoro, chloro, vinyl, allyl, methoxycarbonyl, ethoxycarbonyl, (C1-C4)alkyl, di(C1-C4)alkylamino, piperazino, piperidino, arylperidino, morpholino, pyrrolidino, aziridino, acryloxy, methacryloxy, phenylacetylenyl, and phenylvinyl;
Unsubstituted or mono-substituted heteroaromatic groups, such as furyl, thienyl, and pyrryl subsituted with a substituent selected from the group consisting of (C1-C4)alkyl, and phenyl.
Most preferably, the inventions provides a compound selected from the group consisting of:
2,2-diphenyl-phenanthro (9,10)-2H-[1,4]-oxazine,
2-(p-methoxyphenyl)-2-phenyl-phenanthro (9,10)-2H-[1,4]-oxazine,
2-(p-fluorophenyl)-2-(p-methoxyphenyl)-phenanthro (9,10)-2H-[1,4]-oxazine,
2,2-Bis(p-methoxyphenyl)-phenanthro (9,10)-2H-[1,4]-oxazine,
2-(p-methoxyphenyl)-2-(p-morpholinophenyl)-phenanthro (9,10)-2H-[1,4]-oxazine,
2-(p-methoxyphenyl)-2-(p-piperidinophenyl)-phenanthro (9,10)-2H-[1,4]-oxazine,
2-methyl-2-phenyl-phenanthro (9,10)-2H-[1,4]-oxazine,
2-cyclopropyl-2-phenyl-phenanthro (9,10)-2H-[4]-oxazine,
2,2-diphenyl-6,11-dinitro-phenanthro (9,10)-2H-[1,4]-oxazine,
2-(p-methoxyphenyl)-2-phenyl-6,11-dinitro-phenanthro (9,10)-2H-[1,4]-oxazine,
2,2-Bis(p-methoxyphenyl)-6,11-dinitro-phenanthro (9,10)-2H-[1,4]-oxazine,
2,2-diphenyl-phenanthrolino (5,6)-2H-[1,4]-oxazine,
2-(p-methoxyphenyl)-2-phenyl-phenanthrolino (5,6)-2H-[1,4]-oxazine and
2,2-Bis(p-methoxyphenyl)-phenanthrolino (5,6)-2H-[1,4]-oxazine.
A mild synthetic methodology for preparing the oxazine compound of Formula I is shown below as Reaction A, wherein a disubstituted acrylic acid, a quinone, an azide source such as sodium azide, lithium azide, diphenylphosphoryl azide (xe2x80x9cDPPAxe2x80x9d), or trimethylsilylazide (xe2x80x9cTMSAxe2x80x9d), an organic base including, without limitation, triethylamine, diisopropyl amine, diisopropyl ethylamine, pyridine, piperidine, morpholine, N-alkyl morpholine, 1,8-diazobicyclo[5,4,0]undec-7-ene (xe2x80x9cDBUxe2x80x9d), and a trisubstituted arsen oxide such as triphenyl arsen oxide may be used as reacting agents. The disubstituted acrylic acid may be used to undergo a series of transformations to form aza-ylide intermediate, which may react with a quinone such as phenanthrene (9,10)-dione, phenanthroline(5,6)-dione, to form the desired photochromic oxazine 
The key intermediate of the reaction is a highly reactive isocyanate derivative. The isocyanate may be in situ generated from substituted acrylic azide which in turn may be formed in situ from substituted acrylic acid. The isocyanate is converted to aza-ylide in the presence of catalytic amount of tri-substituted arsen oxide including, without limitation, triphenyl arsen oxide. The arsen ylide reacts immediately with quinone derivative to form the desired oxazine compound and regenerated triphenyl arsen oxide. The generation of the isocyanate from acrylic acid may be conducted by rearrangement of carboxylic azide derivative generated from acid using various reagent combinations under various conditions known in the art including, without limitation, acyl chloride-sodium azide, chloroformate-sodium azide, DPPA, TMSA, in the presence of organic base inclduing, without limitation, triethylamine, diisopropyl amine, diisopropyl ethylamine, pyridine, piperidine, morpholine, N-alkyl morpholine, DBU, and the like. DPPA and TMSA, methyl chloroformate-sodium azide, and methyl chloroformate-lithium azide are preferred azide sources.
One advantage of the above-described methodology is that all of the intermediates may be generated in situ, without purification. The reaction may be conducted either step-wise or, preferably, as a one-pot reaction. In the step-wise reaction, as shown in Reaction A, di-substituted acrylic acid is transformed into di-substituted acrylic acid chloride by treatment with acyl chloride such as thionyl chloride, acetyl chloride, or oxalyl chloride. The acrylic acid chloride is then treated with sodium azide or lithium azide to generate substituted acyl azide, or may be reacted with chloroformate such as methyl chloroformate in the presence of organic base to form mixed anhydride, then treated with sodium azide or lithium azide to generated substituted acyl azide.
Alternatively, substituted acrylic azide may be obtained by reaction with DPPA or TMSA in the presence of organic base. The organic base may be a secondary or tertiary amine including, without limitation, triethylamine, diisopropyl amine, diisopropyl ethylamine, pyridine, piperidine, morpholine, N-alkyl morpholine, DBU, and the like. Upon heating, a arrangement of acyl azide occurs to form the isocyanate derivative of the compound of Formula III. The isocyanate derivative may be reacted with quinone such as phenanthrene(9,10)-dione or phenanthroline(5,6)-dione in the presence of catalytic amount of trisubstituted arsen oxide such as triphenyl arsen oxide to form the desired photochromic oxazine.
The oxazine compounds may be obtained by more efficient, high yielding, one-pot methodology shown as Reaction B. 
In this method, the reaction may be conducted simply by mixing a substituted acrylic acid, an azide source, preferably DPPA or TMS azide, a mild organic base, such as triethylamine, diisopropyl amine, diisopropyl ethylamine, pyridine, piperidine, morpholine, N-alkyl morpholine, DBU, a quinone such as phenanthrene (9,10)-dione, phenanthroline(5,6)-dione, and a catalytic amount of triaryl arsen oxide such as triphenyl arsen oxide, in a suitable organic solvent under heating for a time sufficient to complete the reaction, usually between about 1 and about 15 hours.
Reactive effective amounts of the mixture constituents are used meaning an amount suitable to produce the desired oxazine compound. The amount of trisubstituted arsen oxide may be about 1 mol percent to 20 mol percent, preferably about 2 to 10 mol percent, more preferably about 5 mol percent. The azide source such as DPPA and TMS azide is preferably used in about 1 to 5 equivalents compared with the di-substituted acrylic acid. The amount of organic base used may be about 1 to about 100 equivalents, preferably about 1 to 10 equivalents, more preferably about 2 to about 6 equivalents. Quinone such as phenanthrene (9,10)-dione, phenanthroline(5,6)-dione, may be used in about 0.5 to 1.5 equivalents, preferably about 0.6 to 0.8 equivalents. The preferred ratio of acrylic acid:azide source:base:quinone:triaryl arsenoxide is about 1:1.2:5:0.7:0.05.
Useful organic solvents include, without limitation, benzene, dioxane, tetrahydofuran (THF), toluene, and xylene, and the like and mixtures thereof. Reaction temperatures will vary and typically range from about 40xc2x0 C. to about 150xc2x0 C. In a preferred embodiment, the solvent is nonpolar benzene or toluene and the reaction condition is carried out at about 50 to about 110xc2x0 C. for about 1 to about 15 hours. More preferably, the solvent is toluene or benzene and the reaction is carried out at about 60 to about 80xc2x0 C. for about 2 to 4 hours.
The substituted acrylic acid may be prepared by the either of two reactions, Reactions C and D, illustrated as follows. 
Reaction C, a Hornor-Emmons reaction as described in Tetrahedron, 52(31), 10455-10472 (1996), may be conducted starting from a ketone of Formula V. The resulting 3,3-disubstituted acrylic acid ethyl ester of Formula IV may be hydrolyzed to form disubstituted acrylic acid of Formula II. A, Axe2x80x2 are the same as defined hereinabove.
In reaction D, a ketone is reacted with acetonitrile in the presence of an excess amount of a suitable base including, without limitation, sodium hydroxide to form the 2,2-disubstituted acrylonitrile of Formula V. This process is described in J. Org. Chem., 44(25), 4640-4649 (1979). After hydrolyzation with the base in a suitable organic solvent, followed by acidification, the disubstituted acrylic acid of Formula II may be obtained.
The oxazine compounds of the invention may be used singly, in combination, or in combination with other types of photochromic compounds, including without limitation naphthopyran and spirooxazines, or combinations thereof. The oxazines of the invention may be used in any applications in which organic photochromic substances are typically employed including, without limitation, ophthalmic lenses, windows, automotive transparencies, polymer films, and the like. The oxazines may be utilized in an organic solvent which solvent may be any suitable solvent including, without limitation, benzene, toluene, methyl ethylketone, acetone, ethanol, methanol, tetrahydrofuran, dioxane, ethyl acetate, ethylene glycol, xylene, cylcohexane, N-methyl pyrrolidinone, and the like and mixtures thereof.
Alternatively, the oxazines may be used in an organic polymer host by various means. For example, the oxazine may be dissolved or dispersed into the host material and polymerized with other components of the host material. Alternatively, the oxazine may be incorporated into a coating applied to one surface of the host material. As yet another alternative, the oxazine may be imbibed into or coated onto a surface of the host material.
Preferred host materials are optically clear plastics including, without limitation, polymers, copolymers, or a mixture of polymers. Exemplary host materials include, without limitation, poly(ally carbonate), polyepoxy, polyacrylates, polyethylene, polypropylene, polyvinyl chloride, polymethacrylates, poly (C1-C12)alkyl methacrylates, polyoxy(alkylene methacrylates, cellulose acetate, cellulose triacetate, cellulose acetate butyrate, acetyl cellulose, poly (vinyl acetate), poly (vinyl alcohol), polyurethanes, polythiourethane, polysiloxane, polyamide, polystyrene, and copolymers selected from the group consisting of acrylates, methacrylates, methyl methacrylates, ethylene glycol bis methacrylate, vinyl acetate, vinyl butyral, urethane, thiourethane, diethylene glycol bis(allylcarbonate), diethylene glycol dimethacrylate, diisopropenyl benzene, and the like.
The amount of oxazine used is an amount such that the organic host material to which the photochromic compound, or mixture of compounds, is applied or in which they are incorporated exhibits the desired resultant color. Typically, within limits, the more oxazine used, the greater the color intensity. Generally, about 0.001 to about 20% by weight of the polymer host is used.
Nonphotochromic dyes may be used in conjunction with the oxazines of the invention to adjust the tint. Additionally, antioxidants, UV absorbents, anti-radical agents and the like may also be used to improve photochromic properties.
In solution or in a polymer matrix, the oxazine compounds of the invention are colorless or pale yellow, and rapidly develop an intense coloration under UV irradiation. The oxazines will exhibit a wide range of color when activated by a source of ultraviolet radiation, from orange, reddish-orange, purple, to blue gray. A wide range of fading is also provided, the range being from one half hour to several seconds depending on the structure of the oxazine compound and solvent or matrix used.
One particular advantage of the oxazine compounds of the present invention is that the absorption spectra of the colored form of the activated oxazine typically shows two or three absorption bands covering a wide range in visible spectra. For example, 2-(p-methoxyphenyl)-2-(p-piperidinophenyl)-phenanthro (9,10)-2H-[1,4]-oxazine, upon activation in organic solution or in polymer exhibits a gray color that fades quickly. The compound""s UV-visible spectra showed three bands covered the whole visible-region, which is ideal for application in sunglasses, spectacle lenses, and contact lenses.
The invention will be clarified further by consideration of the following, non-limiting examples.